CANDIDATE: Dr. Stacey Fossey, a veterinarian, is currently enrolled in a dual anatomic pathology residency/PhD program in the Department of Veterinary Biosciences at The Ohio State University (OSU). She has received numerous honors and awards during her undergraduate and graduate training, and has developed substantial leadership skills through 4 years spent in the US Army Medical Service Corps. ENVIRONMENT: Dr. Fossey's mentor, Dr. Cheryl London DVM PhD, is a veterinary medical oncologist with expertise in comparative and translational oncology. Dr. London has extensive experience mentoring veterinarians, graduate students, and clinical fellows in the fields of molecular and clinical oncology as well as comparative medicine using mouse and canine models of human disease. TRAINING PLAN: The K01 SERCA will support completion of Dr. Fossey's doctoral research and subsequent appointment as a Research Assistant Professor. During this time she will develop expertise in mouse pathology and animal models of disease, while transitioning into an independent scientist. PROPOSAL: STAT3 is a known proto-oncogene that enhances cell survival, proliferation, invasion and metastasis of many cancers. Although its involvement has been well documented in carcinomas, the function of STAT3 in sarcomas remains largely unknown. Dr. Fossey has generated preliminary data indicating that STAT3 is constitutively activated in osteosarcoma (OSA) cell lines and tumor specimens. Furthermore, inhibition of STAT3 activity using either a novel small molecule inhibitor (LLL3) or STAT3 siRNA downregulates transcriptional targets of STAT3 and induces OSA cell death. Molecular studies in vitro will be combined with translational work in mice to characterize STAT3 dysregulation in OSA cell lines and primary tissues, assess the effects of STAT3 inhibition alone or with other therapeutics (chemotherapy, HSP90 inhibitor), and determine the biologic activity of STAT3 inhibition against OSA in vivo. In summary, this proposal will clarify how STAT3 dysregulation contributes to the biology of OSA and provide important information regarding the activity of STAT3 inhibitors, laying the foundation for future clinical trials in children. Osteosarcoma (OSA) is the most common bone cancer in children and despite aggressive therapy, 30-40% of affected patients develop metastasis. This study will test the biologic importance and therapeutic potential of a new target for the treatment of OSA, STAT3, by combining studies in the laboratory with those in mouse models of disease, laying the foundation for future clinical work in children with OSA.